#91514: Medical and Illicit Use of Anabolic Steroids

Hypogonadism is a condition defined by insufficient testosterone production necessary for normal growth, development, and sexual function [136]. Androgen deficiency occurs in about 1 in 200 men and is widely underdiagnosed due to cultural taboos regarding "maleness" and sexuality, the absence of patient experience of a normal eugonadal state, and lack of awareness among primary physicians [24,76]. Klinefelter syndrome, an archetype of hypogonadism and its most frequent cause, is also seriously underdiagnosed, with only 25% of men with this condition receiving proper diagnosis [130]. The missed diagnoses of Klinefelter syndrome deprive many men of effective treatment that could enhance quality of life and prevent a lifelong descent into poorer health [40].

Due to the absence of an accepted threshold value of plasma testosterone for defining androgen deficiency and the lack of convincing evidence for an altered androgen requirement in older men, the normal range of serum testosterone in younger adult males is considered to be valid for older men as well [120]. However, based on data obtained from large samples of healthy, nonobese men, the lower limit of the normal range in elderly males is roughly 315 ng/dL (11 nmol/L) for total testosterone and roughly 6.5 ng/dL (0.225 nmol/L) for free testosterone, which corresponds to a bioavailable testosterone of around 140 ng/dL (5 nmol/L) [52,118].

Male hypogonadism stems from testicular disorders that directly reduce testosterone output or from hypothalamic-pituitary disorders that reduce pituitary luteinizing hormone secretion [24,136]. Male hypogonadism is categorized according to etiology; if the origin of pathology occurs at the testicular level, it is considered primary hypogonadism, but if it occurs at the pituitary-hypothalamic level, it is considered secondary hypogonadism. Primary hypogonadism is characterized by elevated levels of luteinizing hormone and follicle-stimulating hormone in response to diminished testosterone (and estradiol and inhibin B) feedback. Secondary hypogonadism is marked by low levels of testosterone associated with low or normal levels of follicle-stimulating hormone and/or luteinizing hormone [76,136].

The most frequent causes of male primary hypogonadism include [5,76]:

Secondary hypogonadism may be caused by [5,76,146]:

Late-onset hypogonadism is considered a mixed primary/secondary type.

Men with hypogonadism experience a myriad of symptoms that reflect the numerous physiologic functions of testosterone. Due to the central role played by testosterone in sexual maturation at puberty, an important determinant to make is whether the onset of hypogonadism occurred before or after puberty [136]. Other symptoms can include weakness, fatigue, lethargy, decreased motivation, loss of self-confidence, decreased energy, insomnia, flushing, and mood changes such as depression or irritability (Table 2) [5].

Diagnosis of hypogonadism involves a combination of medical history, physical examination, and laboratory testing. Diagnosis in elderly men is complicated by the multiple nonspecific symptoms of testosterone deficiency that are features of many other medical conditions. Suspicion based on signs and symptoms must be confirmed with laboratory tests. Serum total testosterone concentration is the most commonly used first-line measure of biochemical male hypogonadism, and when measuring testosterone, bioavailable or free testosterone should be used, not just total testosterone [45]. Other measures, such as testicular size, follicle stimulating hormone, luteinizing hormone, and semen analysis, are used to assist in the differential diagnosis [1].

Injectable testosterone esters have been the foundation of hypogonadism treatment since the 1950s, and the restoration of serum testosterone levels to the normal range using testosterone replacement therapy alleviates or resolves many of the symptoms of hypogonadism [76]. Absolute contraindications to androgen therapy are prostate or breast cancer in men, and ART should be started in men older than 40 years of age only after the exclusion of undiagnosed prostate disease [24]. The Fourth International Consultation for Sexual Medicine found no convincing evidence that ART treatment increases the development or progression of prostate cancer [147]. Meta-analyses have found that ART in men with hypogonadism is associated with an average 1.7 kg gain in fat-free mass and a 1.1 kg gain in body mass, with some studies reporting improvements in maximal voluntary strength and a decrease in fat mass [11]. Treatment of severe hypogonadism increases bone density and strength, but whether treatment of partial hypogonadism with testosterone has the same effect is unknown. Also, whether supraphysiologic doses of androgens have the same effect on bone density remains unresolved [22].

The medical use of anabolic steroids is estimated to have increased 400% between 1995 and 2001, mostly due to the treatment of wasting associated with acquired immune deficiency syndrome (AIDS) [7]. In addition to AIDS, cachexia is prevalent in many other chronic diseases, such as chronic renal failure, hepatic cirrhosis, cancer, and pulmonary disease (Table 3) [7]. The disease course of these conditions is characterized by loss of fat-free mass and increased risk of disability, dependency, and erosion in quality of life. Anabolic steroids are an attractive treatment option because they can restore fat-free mass, muscle strength, and physical function, and they lack the undesirable effects of other cachexia treatments such as the gain in fat mass with megestrol acetate and the high cost and side effects of growth hormone [7,11].

HIV/AIDS

During the early years of the AIDS epidemic, wasting resulting from infection with human immunodeficiency virus (HIV) (weight loss greater than 10% of baseline) was a highly visible sign of the devastating effects of the virus. The gaunt appearance of some of these patients considerably added to the stigma of the diagnosis and created an extra hardship for patients. Despite ongoing improvements in AIDS therapy, HIV-associated wasting remains an issue and may actually be masked by highly active antiretroviral therapy-induced morphologic changes [83]. Wasting is associated with significant morbidity and mortality. A decline to 66% of ideal body weight or 54% of lean body mass is typically fatal, and as little as a 5% weight loss is associated with morbidity and the development of opportunistic infections, even when controlling for CD4+ cell count and other prognostic parameters [83].

A Cochrane review of 13 trials concluded that although anabolic steroids may be useful in the treatment of weight loss in individuals with HIV infection, due to limitations, treatment recommendations cannot be made.

(https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005483/full Last Accessed: October 28, 2022)

Level of Evidence: Meta-analysis

Anabolic steroids should be given to patients with hypogonadism and AIDS-associated wasting. A meta-analysis found that androgen supplementation for three to six months in persons with HIV-associated wasting produced significantly greater gains relative to placebo in fat-free mass, lean body mass, and overall body weight. Testosterone administration was associated with significantly greater improvements in muscle strength than placebo. Testosterone esters were found to produce greater increments in fat-free mass than transdermal preparations [11]. Nandrolone decanoate has been shown to increase overall weight and lean body mass and improve quality of life among patients with AIDS who had lost 5% to 15% of ideal body weight [83]. Oxandrolone increased average weight, appetite, and lean body mass when used alone in patients with HIV wasting, with gains in weight highest among patients combining oxandrolone with progressive resistance training [7,83]. Oral formulations are seldom used because of rapid metabolism and inactivation among class A analogs and liver toxicity among class B and C analogs. However, the orally active testosterone derivative oxandrolone may be suitable for treatment of HIV-associated wasting [83].

Testosterone supplementation in women with HIV infection at doses that elevated plasma testosterone into the high-normal range for women was found to be safe, but weight gain occurred from increases in fat rather than lean body mass [11,83,148]. Further study of the potential role of anabolic steroid therapy in women with wasting syndromes is very much needed [53].

Chronic Obstructive Pulmonary Disease

Similar to patients with HIV, weight loss and muscle wasting in patients with chronic obstructive pulmonary disease (COPD) is associated with increased mortality [119]. Regimens consisting of 250 mg testosterone IM at baseline followed by 12 mg oral stanozolol daily for 27 weeks, nandrolone decanoate, or oxandrolone therapy (20 mg per day) have produced significant improvements in lean body mass and weight, with inconsistent improvement in respiratory parameters [32,101,105]. A possible explanation of the inconsistent improvement in COPD-related parameters is the additive effect of intensive pulmonary rehabilitation, which was only used in some of the trials [103]. Caution is recommended when treating COPD patients with androgens due to the risk of developing polycythemia (overproduction of red blood cells) [7].

Cystic Fibrosis

In a double-blind, placebo-controlled study, patients with cystic fibrosis received 2 mg/kg prednisone every other day for four years [149]. Prednisone helped improve growth and pulmonary function, as well as decrease morbidity. This study was repeated to assess different dosages, and while the use of prednisone was found to be connected to significant improvements in pulmonary health, the dose of 2 mg/kg was found to increase the risk of cataracts, growth retardation, and glucose abnormalities. A 1-mg/kg dosage was associated with fewer complications [149].

Corticosteroid Therapy

Glucocorticoid administration, especially on a chronic basis, is associated with muscle atrophy and a high frequency of low testosterone levels due to generalized suppression of the hypothalamic-pituitary-testicular axis [96]. Controlled trials of testosterone supplementation in men receiving glucocorticoids for bronchial asthma or COPD found that men receiving active drug achieved significant increases in lean body mass and bone mineral density in the lumbar spine and significant decreases in fat mass [11,28,95].

Androgen-deficient men are at increased risk of osteoporosis. Although the extent to which testosterone can prevent or treat osteoporosis in men is unclear, a meta-analysis of eight studies found that IM testosterone moderately increased lumbar bone mineral density, with inconclusive effects on femoral neck bone mineral density and a lack of evidence on the impact on bone fracture [3,112]. Although the efficacy from randomized trials appears modest, if testosterone seems warranted, treatment should begin when severe osteoporosis is present or when osteopenia is coupled with severe testosterone deficiency and/or hypogonadism [62]. A 2016 study elucidated the role of concomitant estrogen deficiency in bone loss in men with hypogonadism [143]. Circulating testosterone levels greater than 200 ng/dL and estradiol levels greater than 10 pg/mL are typically sufficient to prevent decreases in bone mineral density and increases in bone resorption in these patients.

Increases in skeletal mass and bone mineral density during puberty are primarily determined by an increase in bone size and not true volumetric bone mineral density. Androgens stimulate skeletal growth by activation of the AR. Adolescent hypogonadism impairs bone size and maintenance of volumetric bone mineral density, and ART in boys with hypogonadism using a biphasic pattern (i.e., starting at low doses and ending at high-normal doses) is safe and effective in facilitating the achievement of normal height and optimal bone development [26,115].

The anabolic steroids oxymetholone, stanozolol, and danazol, which induce the production of a C1 esterase inhibitor, have been used in the prevention and control of attacks of hereditary angioedema [53,150]. Patients for whom anabolic steroid treatment of angioedema is contraindicated include pregnant women and prepubertal patients due to the risk of virilization [53].

Patients with alcoholic hepatitis with malnutrition were randomized to either oxandrolone plus a high-calorie supplement or placebo and a low-calorie supplement. Significant improvement in liver function and overall survival was observed among the active drug group, and another study found decreased six-month mortality among alcoholic hepatitis patients receiving oxandrolone [66,67]. The use of prednisone in patients with alcoholic hepatitis has been shown to reduce associated mortality [151]. Further studies are needed to fully characterize the effects of anabolic steroids, especially 17α-alkylated agents such as oxandrolone, in this patient population [7].

Transgenderism is an umbrella term for those whose gender identity or expression is different from that typically associated with their assigned sex at birth. This conviction is often coupled with a desire to live in the gender experienced as self, which necessitates hormonal, anatomic, legal, and psychosocial adaptations. Psychologic evaluation of these persons may conclude that sex reassignment (or gender confirmation) surgery will provide relief to the individual. Such persons suffer from gender dysphoria, defined as the extreme and long-standing feeling of being "trapped in the wrong body" [35].

Testosterone is the key hormone in the process of transitioning from female to male for the development of secondary sexual characteristics, and the most commonly used formulations are testosterone esters 100–200 mg IM every two weeks (or 50–100 mg IM weekly) [69]. Following an ovariectomy, testosterone treatment in female-to-male transgender subjects is continued at a dosage level comparable to that given to hypogonadal men [35].

Anabolic steroids stimulate erythrocyte synthesis, which can be helpful in the treatment of hypoplastic anemia. However, use of anabolic steroids in developed countries is likely to be limited by the availability of recombinant human erythropoietin and its analogues [53].

Researchers have known for decades that females are more susceptible to inflammatory autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and psoriasis, and that these female patients experience clinical improvement during pregnancy and a temporary "rebound" exacerbation postpartum [34,152]. These observations suggest an effect of sex hormones on disease, possibly indicating a role for the use of testosterone and the pregnancy hormone estriol in the treatment of multiple sclerosis [34,152]. Preliminary results have shown a favorable safety profile of testosterone and estriol when used in men and women, respectively [34].

Approximately 80% of erectile dysfunction is organic in origin [131]. Research indicates that testosterone therapy improves both erectile function and response to phosphodiesterase type 5 (PDE-5) inhibitors in patients with erectile dysfunction and hypogonadism, and interventional studies have shown that testosterone replacement therapy improves erectile function in men with hypogonadism who have not responded to PDE-5 inhibitor monotherapy. The full therapeutic potential of PDE-5 inhibitors only manifests in eugonadal men [126].

A meta-analysis of the effects of testosterone in men with sexual dysfunction and varying testosterone levels found that testosterone had a modest effect on erectile dysfunction and a moderate-to-large favorable effect on libido. The authors state that the desired benefits of testosterone are often misdirected in that although older men often seek treatment for what is primarily an age-related decline in sexual (mainly erectile) function, erectile dysfunction is mostly neurovascular rather than hormonal in origin and testosterone is unlikely to be helpful in these cases [40]. Also, because hypogonadism is a condition that is common to visceral obesity, metabolic syndrome, diabetes, cardiovascular disease, and erectile dysfunction, these factors should be considered in middle-aged and elderly patients complaining of erectile dysfunction [102].

Short-term studies of postmenopausal women experiencing sexual dysfunction despite sufficient hormone replacement have shown a modest but significant positive effect of transdermal testosterone therapy on libido. However, until longer-term safety studies are available, generalized or long-term use of testosterone therapy in women with sexual dysfunction is contradicted [6,137,153].

A trial evaluating the antidepressant efficacy of 1% testosterone gel 10 g per day among men with refractory depression and low-to-borderline testosterone levels found that testosterone significantly improved both vegetative and affective symptoms of depression, suggesting the possible utility of testosterone as a treatment option for the large underdiagnosed population of depressed men with low testosterone levels [89]. Controlled trials of testosterone in depressed patients with HIV infection failed to replicate the positive effects seen in earlier uncontrolled studies [5]. A meta-analysis of trials regarding the use of testosterone to treat depression in men found that treatment was associated with small improvements in depressive symptoms, but these improvements were not proven to be clinically meaningful. The use of testosterone to treat depression is therefore not recommended [154].

A 2019 systematic review and meta-analysis found oxandrolone to be beneficial in the treatment of burn injuries. Specifically, studies showed that the use of oxandrolone helped to decrease the length of hospital stay and improving growth and wound healing [155].

Abuse and dependence of AAS may be precipitated by muscle dysmorphia [48]. Muscle dysmorphia, also referred to as "reverse anorexia," is a mental condition characterized by pathologic preoccupation with muscularity and represents a variant of body dysmorphic disorder (BDD). Men with muscle dysmorphia believe that they look "puny" or "small," when they actually look normal or even muscle-bound. As a result, they may neglect important social or occupational activities because of shame over their perceived appearance flaws or their need to attend to a meticulous diet and time-consuming workout schedule. Some damage their health by excessively working out, and others report use of AAS in an attempt to get bigger [91]. Many of these men do not experience a resolution of their insecurity and preoccupation over their size through the use of AAS and the resultant increase in muscle mass [46].

Bodybuilders with muscle dysmorphia appear to be distinct from those without muscle dysmorphia, most of whom do not exhibit psychopathology [77]. One study found that compared with occasional and non-AAS using bodybuilders, heavy long-term AAS users were significantly more likely to report preoccupation with being too small and needing to become bigger, as well as a stronger endorsement of conventional and rigid masculine gender roles [46].

Muscle dysmorphia may be both a cause and a consequence of AAS use. Men with body-image pathology may be motivated to use AAS initially and then paradoxically become increasingly concerned about their muscularity even as they are growing bigger on AAS. Muscularity becomes central to their self-esteem, and the thought of loss of muscularity triggers intense anxiety. This phenomenon frequently contributes to the AAS dependency syndrome [14,16,47].

Cultural factors may increase the likelihood of AAS abuse. These include increased competitiveness, body image concerns, and advances in biochemical technology. Younger people can be affected by these influences because of the highly competitive nature of high school and collegiate sports, especially considering that the performance enhancement provided by AAS may be the deciding factor in securing an athletic scholarship or acceptance into professional sports [110].

Evidence exists that body image disorders and associated non-medical AAS use are much more prevalent in Western societies than among other cultures. Several factors are believed to account for these cultural differences, including the emphasis on muscularity and fitness as a measure of masculinity in Western cultures, increasing exposure of men in Western cultures to muscular male bodies in media images, and greater decline in traditional male roles in the West resulting in greater emphasis on the body as a measure of masculinity [125].

As noted, studies comparing personality disorders in AAS-using versus non-AAS using bodybuilders have found a higher prevalence of cluster B personality disorders of the histrionic and antisocial type among AAS users, higher scores among AAS users on measures of pathologic narcissistic traits (e.g., exhibitionism, entitlement, exploitativeness) and lower ratings for empathy. A significantly higher proportion of self-reported memories of childhood sexual or physical abuse have been found among AAS abusers [39,144].

Compared with occasional AAS users and non-AAS users, men with AAS dependence have been found to be older and more muscular, more likely to have had a single parent by 13 years of age, more likely to report substance abuse in a first-degree relative, less educated, and more likely to have a history of conduct disorder. A history of non-alcohol substance dependence, particularly with opioid abuse and dependence, largely contributes to differences in lifetime substance abuse and dependence in AAS dependent individuals [46,51].

Regular AAS use produces a withdrawal syndrome characterized by both affective and hypogonadal symptoms. AAS abusers with more severe withdrawal symptoms following initial cycles of AAS use may become increasingly prone to resume AAS to prevent these symptoms. This heightened sensitivity may be mediated by a particular vulnerability residing in the hypothalamic-pituitary-thyroid (HPT) axis, opioidergic pathways, or other neurotransmitter mechanisms [48].

Some persons who abuse AAS to increase their muscle mass have experienced physical or sexual abuse. One study of AAS-abusing male weightlifters found that 25% reported memories of childhood physical or sexual abuse [75]. Female weightlifters who had been raped were twice as likely to use AAS as those who have not been raped. Almost all of these women who reported being raped also reported markedly increasing their bodybuilding activities after the attack, believing that increased size and strength would discourage further attacks [75,158]. Thus, compulsive weight lifting and AAS abuse may represent a form of response to the trauma of sexual assault [36].

"Cycling" entails taking multiple doses of steroids over a specific period of time, stopping for a period, and starting again [75,162]. The periods of AAS use interspersed with periods of recovery/abstinence are intended to allow the endocrine system to return to homeostasis [23]. Before a cycle is initiated, the length, dosages, and compounds to be used are anticipated and obtained. The anticipated plan is usually adhered to, although cycles can be altered to change the dosage or avoid side effects [23].

"Stacking" involves combining two or more types of steroids based on the theory that different steroids interact to produce a greater effect on muscle size than the effect of each drug alone. Stacks usually combine compounds with contrasting properties, such as long- and short-acting agents, aromatizable and reducible agents, or oral and injectable drugs. They also usually include ancillary compounds intended to intensify the AAS effect or minimize the side effects of AAS and may even include compounds designed for veterinary use [75,123]. Stacking usually involves using oral and IM preparations at progressively higher doses until 40 to 100 times the typical physiologic levels is achieved; the use of five different drugs is typical [39]. The goal of stacking is to "activate more receptor sites" than is possible with single agents [123]. Because of the complex nature of stacking regimens, AAS abusers may have a "coach" to help them devise the schedule and the regimen [39].

"Pyramiding" is a practice whereby users slowly escalate the intensity of the steroid regimen to reach a peak amount at mid-cycle, and then gradually taper the dose toward the end of the cycle [75,162]. Users often pyramid their doses in cycles of 6 to 12 weeks, in some cases followed by a second cycle of training without drugs [75]. Pyramiding is performed with the goals of avoiding plateauing (i.e., developing tolerance to a specific steroid), allowing the body to adjust to high-dose AAS, and minimizing withdrawal symptoms when steroid use is suspended [75; 123).

"Plateauing" is a technique by which steroids are staggered, overlapped, or substituted with another type of steroid to avoid developing tolerance [156,162].

With the planned cycling, healthy diet, ancillary drugs, blood work, and mitigation of harm via route of administration, AAS abuse involves more planning and organization than other illicit drug use. AAS users are likely to have substantial amounts of AAS on hand for long-term personal use in order to achieve the sustained supraphysiologic levels of steroid hormones. In one study, many respondents used up to 12 methandrostenolone tablets (5 mg each) per day, with some using more than 20 tablets, necessitating an initial possession of 1,000 tablets or more for personal use [23].

Nandrolone, oxandrolone, testosterone, stanozolol, methandienone, and methenolol are the most frequently abused AAS agents. IM formulations of these drugs are preferred over oral formulations, and combinations of androgens are used more frequently than single agents [21]. In one survey, the average total AAS dose of testosterone was 500–1,000 mg per week. The highest dosage of testosterone used for four or more weeks was 797.5 mg per week, and 95% of users injected their steroids [23].

Excessive and inappropriate aggression is the behavioral response most often associated with AAS abuse [98]. It appears that chronic AAS use modifies homeostatic processes, affects neurotransmitters, and can cause changes in brain structures, leading to increased anxiety and tendency for aggressive behavior or poor impulse control [163]. The "roid rage" from high AAS doses may be the manifestation of an AAS-induced hypomanic syndrome that begins with feelings of invincibility and worsens as dosages increase [29]. These rages can result in property damage, self-injury (including reckless driving or crashing cars), assaults, marriage break-ups, domestic violence, child abuse, suicide, and attempted murder or murder [17,19,20,61,85,100,127]. The impulsive perpetration of homicide and attempted homicide has been documented as occurring in male AAS users with benign premorbid psychiatric histories, no evidence of antisocial personality disorder, and no history of violence, with steroid use playing a necessary, if not primary, role in the violent acts [85]. One group of men who may take high-dose AAS are those working as security officers or nightclub bouncers; under the influence of the drug, they may be provoked into a rage and engage in violent behavior resulting in injury or death [25,31].

Intimate relationships may represent the most likely setting where AAS-induced aggression and violence manifest. Choi and Pope found that AAS abusers reported significantly more verbal and physical aggression and violence toward their partners when using AAS than when not using AAS. When not on an AAS cycle, the AAS users off-drug did not significantly differ from nonusers [19]. These findings support anecdotal evidence that partners of AAS users may be at risk of serious injury from users while they are on-drug.

The prevalence of AAS-induced rages is unknown. Although prolonged high-dose use of AAS is the most common antecedent, not all people taking high doses develop steroid rages, and reports exist of rages occurring with low-dose AAS use [25]. Although serum testosterone level is correlated with aggressiveness, the relationship between supraphysiologic doses of AAS and aggressive and/or violent behavior is complex. Pope, Kouri, and Hudson observed that most normal males given 600 mg testosterone did not experience psychiatric symptoms [88]. The overall effect was of increased manic symptoms, which was also variable, with few participants reporting increased aggression levels.

It is also likely that some violent rages occurring in AAS abusers might be better understood as part of a paranoid psychotic state. Psychotic symptoms associated with AAS generally unfold in persons consuming more than 1,000 mg testosterone per week [86]. Classic presentations include grandiose and paranoid delusional states occurring in the context of an overtly psychotic or manic episode. The symptoms usually resolve within a few weeks after AAS discontinuation but may persist for as long as one month, even when antipsychotic medication is administered [39].

Many studies have associated depressive symptoms and reports of suicide with AAS abuse, especially during withdrawal from AAS at the end of a "cycle" that is likely attributable to HPT suppression [25]. Similar to highly aggressive behavior, depressive symptoms appear to be idiosyncratic, with occasional individuals showing marked symptoms and others showing none [47]. The risk of depression and suicide remain heightened even in former AAS users, suggesting that psychiatric disorder may either predispose a person to or result from AAS use [25]. Suicide has been found to be significantly more common among former AAS users than among other types of substance users, and a study of former elite Swedish male athletes found that former AAS users were significantly more likely to report having sought treatment for psychiatric symptoms compared to nonusers [47,81].

Recovery from long-term hypothalamic-pituitary-adrenal-axis suppression with continued AAS use may take weeks to months depending on the dose and duration of AAS use and in some ways resembles the glucocorticoid withdrawal syndrome [43]. The user experiences symptoms of androgen deficiency during the period immediately after AAS discontinuation, which can include loss of sexual desire and function, lack of energy, depressed mood, and hot flashes (Table 5). Major mood disorders such as mania, hypomania, and depression are experienced by as many as 23% of users, many of whom resume AAS use due to an inability to tolerate the psychologic symptoms of withdrawal [21,43]. Other symptoms are related to the loss of the AAS-induced positive psychologic effect and include listlessness, apathy, loss of appetite, decreased libido, low self-esteem, anxiety, difficulty concentrating, and mood swings [25]. Withdrawal can also be associated with violent behavior and rage, and although severe steroid withdrawal is likely to be less of a problem in athletes due to more circumscribed phases and gradual dose reduction, body builders or weight trainers are likely to have greater problems during the course of withdrawal as a result of a loss of body image and enhanced musculature [25].

The effects of AAS use are infrequently documented in women relative to male AAS abusers. However, female AAS users have been found to experience hypomanic symptoms during use, depression upon discontinuation, and a body image distortion similar to the "reverse anorexia" seen in some male AAS abusers [110].

Supraphysiologic doses of AAS can produce a range of adverse cardiovascular effects, including hypertension, cardiomyopathy, left ventricular hypertrophy, dyslipidemia, myocardial ischemia, adverse effects on coagulation and platelet aggregation, and arrhythmias. Some of these effects, such as hypertension, dyslipidemia, and coagulation abnormalities, remit after AAS use is discontinued, but effects such as atherosclerosis and cardiomyopathy are likely irreversible. These effects have been blamed for numerous premature deaths among athletes between 20 and 40 years of age known or believed to have used AAS, either from cardiac disease or cerebrovascular accidents. Older former AAS users now entering the age bracket of increased cardiovascular risk may display an increased rate of serious cardiovascular events [30,47].

Potential mechanisms of cardiovascular toxicity from AAS use include atherogenic, thrombotic, vasospastic, and direct myocardial injury [30,106]. Steroids contribute to the development of cardiovascular morbidity by causing substantial alterations in lipid metabolism, partly by changing the levels of lipoproteins that carry cholesterol in the blood [30]. Oral AAS increase the level of low-density lipoprotein and decrease the level of high-density lipoprotein [75].

The risk of cardiotoxicity among men with hypogonadism receiving testosterone is clinically negligible, and although the risk of long-term testosterone in aging men is largely unknown, exogenous testosterone treatment appears largely beneficial, partially explained by the aromatization of testosterone to estradiol [38,65].

The reduced fertility associated with AAS use stems from gonadotropin suppression, which results in azoospermia, abnormalities in sperm motility and morphology, and testicular atrophy. Some studies have documented the irreversibility of these effects after AAS use has ceased, while other studies have noted a return to normal testicular function after AAS discontinuation [7].

Long-term AAS use suppresses the HPT axis, and AAS users often experience hypogonadism at the conclusion of an AAS cycle. Normal HPT function usually recovers spontaneously within several weeks to several months, but some AAS users experience hypogonadism for more than a year [47]. AAS abuse disrupts the normal production of endocrine hormones, resulting in both reversible and irreversible changes. Potentially reversible changes include reduced sperm production and testicular atrophy, while irreversible changes include male-pattern baldness and gynecomastia in men [75]. AAS use can cause acne, cysts, and oily hair and skin [75].

AAS users who inject anabolic steroids may use nonsterile injection techniques or share contaminated needles with other abusers. Some steroid preparations are manufactured illicitly under nonsterile conditions, and these factors increase the risk for acquiring serious and potentially life-threatening viral infections such as HIV and hepatitis B and C [21]. AAS abusers can also develop endocarditis, a bacterial infection that causes a potentially fatal inflammation of the inner lining of the heart, or bacterial infections at the injection site, causing pain and abscess formation [75].

Use of the orally active 17α alkylated AAS is associated with serious hepatic complications that include peliosis hepatis, intrahepatic cholestasis, hepatocellular adenomas or carcinomas, hepatic angiosarcomas, and spontaneous hepatic rupture [47]. Although these risks are greater with longer-duration AAS use, the overall prevalence of adverse hepatic complications from illicit AAS use is likely low [47]. Nonetheless, reports of hepatocellular adenoma following AAS abuse among bodybuilders suggest this group is at heightened risk of developing sex hormone-related tumors and should be monitored annually with ultrasound examination [104].

Orthopedic complications, mostly tendon ruptures, have been reported with AAS use [110]. Excessive muscle hypertrophy without concurrent adaptation in the associated tendons and connective tissues may place users at heightened risk for tendon injury and rupture from the abnormal stress placed on joints and tendons [21].

The use of AAS by women who desire their anabolic effects has been found to produce consistent masculinizing side effects that are predictable, severe, and often irreversible long after AAS cessation. Physiologic changes include deepening of the voice, clitoral hypertrophy, menstrual irregularities, decreased body fat, and increased facial hair. Behavioral changes include increased libido, aggressiveness, and appetite. Women may also experience acne and changes in breast size and body hair distribution [56,75,138].

For those who are not proficient in English, it is important that the patient history and information regarding the risks associated with the use of AAS be obtained in the patient's native language, if possible. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Interpreters can be a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers who ultimately enhance the clinical encounter. In any case in which information regarding diagnostic procedures, treatment options, and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.

In order for patients to maintain abstinence from AAS and to prevent relapse, they may require support and encouragement in changing their lifestyle. This can entail switching gyms and changing workout friends, competitive events, and/or sports. Discussions of body image issues may be necessary. Some patients will benefit from referral to specialists who can help them develop healthy fitness regimens. Providers working with AAS-dependent patients are advised to form strong relationships with experts in sports medicine for advice and referral [29].